To date, investigations into canine glioma brain tumors have been superficial and limited in their comparison towards their human counterparts. The on-going characterization of canine glioma-derived tumor initiating cells (TICs) not only provides an additional species for comparison of human glioma TICs, but also makes possible the direct comparison of canine glioma TICs, normal adult canine neural stem cells (NSCs), and canine embryonic NSCs. Many laboratories have attempted to establish links between embryonic and adult neural stem cells and glioma derived TICs; the belief being that such a comparison may reveal key regulatory pathways responsible for neoplastic transformation of glial progenitors or mature glial cells in the adult, or offer insights for novel therapies. Embryonic neural stem cells exit from toti- or pluripotent embryonic stem cells into temporally defined periods of proliferation, neuronal, and then glial differentiation, governed by pathways which may be overrepresented (in the case of proliferation) or repressed (in the case of neuronal or glial differentiation status) in glioma-derived tumor stem cells. During the period of physiologic embryonic neural stem cell proliferation, these cells are refractory to exogenous differentiation cues, which in neural stem cells derived during mid- and late-gestation trigger neuronal and glial differentiation, respectively. This blockade of differentiation may highlight key common pathways preventing differentiation or exit from cell cycle in glioma-derived tumor initiating cells. The domestic dog represents the only model which allows all of these facets to be studied within the same species, and in respect to glioma TICs and adult NSCs, syngeneic samples from the same individual. As the ability to interrogate the canine genome increases, the clearly defined breed predispositions in regard to canine gliomagenesis may elucidate biologically relevant genomic alterations found in human glioma, enhancing our ability to classify this heterogeneous neoplasm by molecular biology, which may greatly improve our understanding over traditional pathologic grading schema.